A successful virus infection usually involves entry into the cell; uncoating, expression and replication of the genome; assembly and release of infectious virus particles; and defense against specific and non-specific host immune mechanisms. Some genes are required for replication in any cell, whereas others are only important in certain ones. Still other genes have no role in vitro and are advantageous only during animal infection. Studies during the past year have contributed to our understanding of the mechanism of virus entry. Evidence was obtained that both intra- and extracellular forms of vaccinia virus fuse with the cell membrane in a pH independent manner. A large number of genes that are not required for growth in tissue culture have been identified. The conservation of these genes in vaccinia virus and other members of the orthopoxvirus genus signifies that the protein products have an important role in virus-host interactions. We have given the name virokine to one class of such proteins that are secreted from infected cells. The first member of this class is the vaccinia virus growth factor, VGF. We have identified two additional members. One is a 35,000 molecular weight protein that has both structural and functional similarities to the human complement 4b binding protein. The viral protein is able to bind to C4b and to block the classical complement pathway in vitro and may provide defense against the host immune system. Another protein of this class has a molecular weight of 14,000. Although the function of the protein of this class has a molecular weight of 14,000. Although the function of the protein is unknown, deletion of the gene attenuates the pathogenicity of vaccinia virus for mice.